This invention relates to radio-diagnostic agents for use in tissue imaging. More particularly, it relates to a process for preparing improved skeletal imaging products.
Scintigraphic skeletal imaging and similar radiographic techniques for visualizing other tissues are finding ever-increasing application in biological and medical research and in diagnostic procedures. Generally, scintigraphic procedures involve the preparation of radioactive agents which, upon introduction into a biological subject, become localized in specific organs, tissue, or skeletal structures that are under study. When so localized, traces, plots, or scintiphotos of the distribution of the radiographic materials can be made by various radiation detectors, e.g., traversing scanners and scintilation cameras. The distribution and corresponding relative intensity of the detected radioactive material not only indicates the position occupied by the tissue in which the radionuclide is localized, but also indicates the presence of aberrations, pathological conditions, and the like.
In general, depending on the type of radionuclide used and the organ of interest, a scintigraphic imaging agent as used in a hospital comprises a radionuclide, a carrier agent designed to target the specific organ, various auxiliary agents which affix the radionuclide to the carrier, water or other delivery vehicles suitable for injection into, or aspiration by, the patient, physiologic buffers and salts, and the like. The carrier attaches or complexes with the radionuclide, and localizes the material in the location where the carrier naturally concentrates in a biologic subject.
Technetium-99m (.sup.99m Tc) is a radionuclide which is widely known for use in tissue imaging agents. This radionuclide is conveniently available commercially in the oxidized pertechnetate form (.sup.99m TcO.sub.4.sup.-, hereinafter "pertechnetate-Tc99m"). However, the technetium in pertechnetate has a valance state of +7 and, thus, will not complex with the most commonly used carriers for radionuclide tissue imaging. This problem is easily overcome by reducing the technetium to what is believed to be the +3, +4, and/or +5 oxidation state. Thus, technetium-labeled imaging agents are generally prepared by admixing pertechnetate-Tc99m isotonic saline solution with a technetium reductant (reducing agent) such as the stannous, ferrous, or chromous salt of sulfuric or hydrochloric acid, and the desired carrier agent for targeting the organ of interest. For example, organophosphonates are known as suitable carrier agents which target technetium radionuclide to bone tissue. U.S. Pat. No. 3,983,227, Tofe and Francis, issued September 28, 1976, discloses the use of reducing salts with radioactive pertechnetate-Tc99m solutions and organophosphonate bone-seeking carriers to prepare skeletal imaging agents.
Technetium-containing scintigraphic imaging agents are known to be unstable in the presence of oxygen, primarily since oxidation of the reductant and/or the technetium destroys the reduced technetium/targeting carrier complex. Accordingly, such imaging agents are generally made oxygen-free by saturating the compositions with oxygen-free nitrogen gas or by preparing the agents in an oxygen-free atmosphere. Stabilization of imaging agents can also be achieved through chemical means. German Offenlegungsschrift 2,618,337, Tofe, published November 11, 1976, discloses the use of ascorbate stabilizers with technetium imaging agents. U.S. Pat. No. 4,232,000, Fawzi, issued Nov. 4, 1980, discloses the use of gentisyl alcohol as a stabilizer for technetium imaging agents. Similarly, U.S. Pat. No. 4,233,284, Fawzi, issued November 11, 1980, discloses the use of gentisic acid as a stabilizer.
Commercial products for use in skeletal imaging are generally provided in liquid or dry powder mixture "kits" with vials containing phosphate or phosphonate bone seeking carriers. Skeletal imaging agents are formed by adding pertechnetate-Tc99m, in physiological saline, to such kits. Osteoscan-HDP.sup.R, which comprises the disodium salt of methanehydroxydiphosphonic acid (HMDP), stannous chloride, and gentisic acid stabilizer, is one example of a freeze-dried (lyophilized) skeletal imaging kit. Generally, such kits are produced by a process which includes the steps of:
(1) adding solid ingredients to sterile water, PA1 (2) metering of the resulting bulk solution into individual vials, PA1 (3) lyophilizing the solution in the vials, and PA1 (4) packaging. PA1 (1) preparing an aqueous solution of a diphosphonate, a stannous reductant, and, optionally, a gentisate stabilizer; PA1 (2) adjusting the solution formed in step 1 to a pH within the range from about 4.2 to about 4.8; and PA1 (3) lyophilizing the pH-adjusted solution. PA1 (1) a diphosphonate carrier; PA1 (2) a stannous reductant; and, optionally, PA1 (3) a gentisate stabilizer. PA1 (a) an amount of diphosphonate carrier sufficient to target the technetium in a pertechnetate solution containing from about 1 to 400 mCi of technetium-99m; PA1 (b) an amount of stannous reductant sufficient to reduce the technetium in a pertechnetate solution containing from about 1 to 400 mCi technetium-99m, and PA1 (c) an amount of gentisate stabilizer sufficient to prevent oxidation of the reductant and the reduced technetium-99m.
For Osteoscan-HDP.sup.R, the pH of the solution, prior to lyophilization in the manufacturing process, is 3.9. It has now been discovered that adjusting the pH of the bulk solution within a certain pH range produces a freeze-dried skeletal imaging kit that, when reconstituted with pertechnetate-Tc99m solution, forms a skeletal imaging agent with improved performance. Thus, it is an object of this invention to provide an improved process for preparing imaging kits.